Although drug-eluting stents (DES) have significantly reduced the incidence of restenosis and the need for repeat revascularization,1 DES restenosis still occurs in a sizeable proportion of patients.2 The most widely used classification for in-stent restenosis (ISR) has been proposed by Mehran et al.3 This classification has prognostic implications, as the diffuse pattern of ISR is associated with a worse prognosis and a higher incidence of target vessel revascularization as compared to the focal pattern.4–6

Experimental and clinical studies have shown that ISR is a complex and multifactorial process in which the inflammatory response of the arterial wall to stent deployment seems to play a pivotal role.7–9 Both baseline and periprocedural changes of C-reactive protein (CRP) levels have been shown to predict angiographic restenosis after bare-metal stent (BMS) implantation, but its ability to predict restenosis after DES is still controversial.10–20 In particular, baseline CRP levels seem to be associated predominantly with major adverse cardiac events, but not with angiographic ISR.16,18,20 The predictive value of high CRP serum levels, however, might be confined to the diffuse pattern of ISR, which reflects a more aggressive inflammatory response of the vessel wall against the implanted stent. Thus, we assessed variables associated with ISR pattern after DES implantation among clinical, angiographic, procedural and laboratory data, including baseline CRP serum levels.

Methods

Our database (Cardio-planet V.3.0.8, Ebit Aet S.p.A, Genoa, Italy) was searched retrospectively for cases of ISR occurring after DES implantation at our catheterization laboratory from January 2007 to December 2009. At our institution, each patient undergoing percutaneous coronary intervention (PCI) is recorded in the database, which collects clinical, angiographic and procedural data. Of note, in that period of time, a total of 2,161 patients underwent PCI. Among the total number of PCIs, we retrieved 273 cases of ISR, with 149 of an underlying BMS and 124 of an underlying DES. We excluded 35 patients with conditions which may have affected baseline CRP levels at the time of the first PCI: acute coronary syndrome (n = 21); severe chronic heart failure (New York Heart Association class III–IV) (n = 5); systemic inflammatory diseases such as acute and chronic infections (n = 2); autoimmune diseases (n = 2); liver diseases (n = 1); neoplasia (n = 1); evidence of immunologic disorders (n = 1); use of anti-inflammatory or immunosuppressive drugs (n = 1); recent (

mTOR inhibitor-DES types showing ISR included sirolimus-eluting stents (SES) (Cypher; Cordis, Johnson & Johnson, Miami Lakes, Florida), zotarolimus-eluting stents (ZES) (Endeavor; Medtronic, Minneapolis, Minnesota), and tacrolimus-eluting stents (TES) (Janus; Sorin Biomedica, Italy). We also assessed the time interval between first DES implantation and angiographic ISR detection and the indication for restudy was assessed at the time of PCI for ISR.

Coronary angiograms were independently reviewed by two expert angiographers who had no knowledge of patients’ clinical characteristics and biochemical results. Quantitative angiography was performed using a validation detection system (CMS; Medis Medical Imaging Systems, The Netherlands). Minimal luminal diameter, reference diameter and percent diameter stenosis were measured in identical views before percutaneous balloon angioplasty and immediately after stent deployment at the time of DES implantation. Angiographic restenosis after DES implantation was defined as diameter stenosis of ≥ 50% occurring in the previously stented segment or 5 mm segment proximal or distal to the stent. Pattern of angiographic restenosis was defined according to simplified Mehran classification as focal or diffuse.3

Data distribution was assessed by the Kolmogorov–Smirnov test. CRP levels had a skewed distribution and were expressed as medians and interquartile ranges. Other continuous variables were expressed as means ± standard deviation, and dichotomous variables as percentages. CRP levels were also categorized by tertiles for graphic presentation. Comparisons were performed by T-test, Mann-Whitney test or c2-test, as appropriate. Correlations between variables were performed using the Pearson or Spearman correlation test, as appropriate. A Chi-square test for trend was performed in order to compare the rate of diffuse ISR pattern according to CRP tertiles. Multivariable analyses were performed using logistic regression analysis in order to assess independent predictors of ISR pattern. At this scope, in the model we included all variables showing a significant or borderline association at univariate analysis (p-values

Results

Clinical and laboratory characteristics of the overall study population and according to angiographic pattern of ISR are summarized in Table 1, while baseline angiographic and procedural data are shown in Table 2. We included 72 patients (age, 65 ± 9 years; male, 64%). 39% of patients (n = 28) were diabetic, and 18% of patients (n = 13) showed 3-vessel disease at coronary angiography. In our population, 35% of patients (n = 25) had an ISR of SES, 32% (n = 23) of ZES, and 33% (n = 24) of TES. Indication for re-study was due to a non-ST-elevation myocardial infarction (NSTEMI) in 10 patients (14%), effort angina with signs of ischemia in 47 patients (65%), and silent ischemia in 15 patients (21%). 34 patients (48%) presented with a focal pattern of ISR, whereas 38 patients (52%) presented with an ISR diffuse pattern. Mean time to angiographic restenosis was 184 ± 111 days in the focal ISR group and 199 ± 105 days in the diffuse IRS group (p = 0.8). Of note, mean time to restenosis was similar according to DES type (p = NS).

Patients presenting with a diffuse ISR pattern showed a trend to have more frequently a previous history of myocardial infarction (p = 0.06) as compared to those presenting with a focal ISR pattern. Finally, patients with a diffuse ISR pattern had significantly higher CRP serum levels as compared to those with a focal ISR pattern [2.7 mg/L (1.9–3.4 mg/L) versus 4.6 mg/L (3.7–6.4 mg/L); p with a diffuse ISR pattern as compared with focal ISR pattern tended to be more frequently an NSTEMI (21% versus 6%; p = 0.06). Of note, patients with CRP serum levels in the third tertile had a higher rate of diffuse ISR pattern (13% versus 26% versus 61%; p for trend = 0.0001) as compared to patients with CRP serum levels in the first and second tertiles (Figure 2). At multivariate analysis, CRP serum levels were the only independent predictor of diffuse ISR angiographic pattern (OR, 2.5; 95% CI, 1.4–4.3; p = 0.001) (Table 3).

Discussion

In this study, we demonstrate that baseline CRP serum levels are associated with a diffuse angiographic pattern of ISR after coronary DES implantation. DES have considerably reduced restenosis and TVR rates as compared to BMS.1 The reported benefit with DES, however, is not the same across various clinical or angiographic subgroups of patients and may depend on procedural variables. Indeed, the ISR rate is particularly high among patients with diabetes mellitus and renal insufficiency.21–25 Along with patient-related or procedure-related mechanisms, inflammation may also play a role in ISR after DES. Experimental and clinical studies have shown that ISR is a complex and multifactorial process strongly influenced by the inflammatory response of the arterial wall to stent deployment. In particular, after coronary stenting, inflammatory mechanisms play a crucial role in the pathogenesis of neointimal proliferation, including sustained leukocyte infiltration in the arterial wall and smooth muscle cell migration and proliferation.7–9,26 New evidence suggests that inflammatory reaction to polymers after DES implantation may actively participate in this complex process.27,28 The role of the individual predisposition to inflammation as assessed by both baseline CRP levels and post-procedural rise of CRP levels has been widely explored in the BMS era, showing an association of CRP with both angiographic ISR and major adverse clinical events,11 especially in statin-naive patients.29 Conversely, data concerning the predictive role of baseline CRP serum levels for ISR after DES are controversial. In particular, baseline CRP levels seem to be associated predominantly with major adverse cardiac events, but not with angiographic ISR.20 To date, the largest study addressing this issue in the DES era has been performed by Park et al,18 who assessed the association of preprocedural CRP levels with angiographic restenosis and adverse clinical events after DES implantation, showing a significant association between preprocedural CRP levels and major coronary events. However, they failed to find an association between preprocedural CRP levels and ISR. Interestingly, the same authors recently showed that baseline CRP levels > 3 mg/L predicted long-term (4 years) death/myocardial infarction and stent thrombosis, but not target vessel revascularization.20 Moreover, Kang et al failed to show a significant correlation between the baseline value or periprocedural change in CRP levels and angiographic late loss.19 In contrast, Gaspardone et al showed that higher 48-hour post-procedural increases of CRP were significantly correlated with clinical outcomes and in-segment restenosis in both patients receiving DES and BMS.17 Finally, Dibra et al found that in the BMS subgroup, but not in the DES subgroup, patients with ISR had a greater change in CRP levels from baseline compared to those without ISR.14 Taken together, these observations seem to negate a role of CRP in angiographic ISR after DES, although they suggest a role of CRP for risk assessment of future clinical events after DES implantation. The predictive value of high baseline CRP serum levels, however, might be confined to the diffuse pattern of ISR, which reflects a more aggressive inflammatory response of the vessel wall against the implanted stent and is usually associated with an acute clinical presentation, as also observed in our study.30 Our aim, indeed, was not to assess the predictive role of baseline CRP levels for the degree of ISR after DES implantation, but to investigate the role of baseline inflammatory reactivity in the diffuse ISR pattern which occurs despite drug elution. In particular, our data seem to suggest that when baseline inflammatory reactivity is pronounced, it may be able to overcome the antiproliferative and anti-inflammatory effects of the eluted drug, resulting in a diffuse pattern of ISR. Thus, high baseline CRP serum levels may be useful to identify patients undergoing DES implantation who probably require adjunctive anti-inflammatory therapy. Accordingly, administration of drugs with anti-inflammatory properties, such as statins or steroids, have been suggested to reduce the risk of major adverse cardiac events and ISR in the BMS era,31,32 especially in those patients with high inflammatory reactivity.29,32 Of note, the role of systemic anti-inflammatory therapies as adjuncts to the local effect of DES has not yet been tested. Finally, as ISR pattern is relevant for the clinical outcome, it should be taken into account by future prospective studies regarding prognostic utility of CRP in the DES era.

Study limitations. First, we decided not to include BMS restenosis, as we were interested in assessing the role of CRP in the DES setting. Indeed, many studies have already reported an association of baseline CRP serum levels with ISR after BMS implantation. Second, ISR angiographic pattern was not predicted by stent type. However, given the relatively small numbers of patients according to DES type, an association between DES type and ISR pattern cannot be excluded. Furthermore, the sample size is small, but we have been able to show a significant difference in this small sample population. Of note, this series is representative of a 3-year interventional activity of a high-volume center, where DES ISR was only 3.4% of overall PCIs. However, due to the low number of patients presenting with a diffuse pattern of restenosis, we cannot exclude a problem of over-modeling in the statistical analysis. Finally, increased CRP levels are also associated with an enhanced coronary atherosclerosis progression. Moreover, a study of ISR with BMS showed lipid-laden tissue by optical coherence tomography when the follow-up was extended more than 6 months.33 Interestingly, recent angioscopic findings showed atherosclerotic yellow neointima and cholesterol-laden plaque inside DES restenotic tissue, suggesting that atherosclerotic disease progression may contribute to DES ISR (nouveau atherosclerosis).34 Yet, as the aim of our study was to evaluate the predictive value of CRP on angiographic ISR pattern after m-TOR inhibitor DES, we did not perform intracoronary imaging analyses. Further studies are needed to evaluate the relationship between CRP levels and mechanisms (intimal proliferation versus nouveau atherosclerosis) of ISR, assessed by serial intracoronary imaging analysis.

Conclusion

Baseline CRP serum levels are associated with a diffuse ISR pattern after DES implantation. These findings suggest that baseline inflammatory reactivity may contribute to aggressive restenosis occurring despite drug elution. Future studies are needed to better elucidate the prognostic role of CRP in DES-treated patients.